Anti-Hu antibody associated paraneoplastic neurological syndrome in a child with ganglioneuroblastoma: A rare case report and literature review.

RATIONALE: Paraneoplastic neurological syndrome with anti-Hu antibody (Hu-PNS) is a neurological disorder that occur in patients with malignancy. The syndrome has a wide range of presentations and can present before diagnosis of primary malignancy. Familiarity with these paraneoplastic neurological syndromes can help early recognition and take appropriate regimens. PATIENTS CONCERNS: Diagnosis and treatment of Hu-PNS. DIAGNOSES: This is retrospective study that analyzed the clinical data of this case. Through retrospective analysis and targeted antibody screening, serum anti-Hu antibody was detected. Subsequent spinal imaging revealed a mass in the paraspinal region, which was confirmed as ganglioneuroblastoma by pathologic examination. INTERVENTIONS: The child was treated with a course of intravenous immunoglobulin and radical surgical operation without chemotherapy. OUTCOMES: The neurological symptoms were gradually improved and no signs indicate disease progression or tumor recurrence. LESSONS: Hu-PNS has rarely been reported in children with ganglioneuroblastomas. They can mimic non-neoplastic processes, making detection and diagnosis difficult. Serum and/or cerebrospinal fluid onconeural antibody can strongly indicate occult cancers. Early detection of paraneoplastic neurological syndromes can help take appropriate regimens and improve prognosis.

[Paraneoplastic Disorders of Peripheral Nervous System].

Paraneoplastic disorders of the peripheral nervous system are immune-mediated neurological syndromes associated with tumors. Several clinical phenotypes have been associated with these disorders. Sensory neuronopathy is the most well-known clinical phenotype, and is caused by neuronal cell injury to the dorsal root ganglia. Symptoms of the peripheral nervous system usually lead to the discovery of tumors. Antineuronal antibodies are occasionally identified in the serum and/or cerebrospinal fluid of these patients. The prevalence of small-cell lung cancer is notable in these patients. Early tumor resection, coupled with the initiation of immunotherapy, may prove effective in improving and stabilizing clinical symptoms.

Clinical Presentation, Management, and Diagnostic Performance of 2021 Criteria for Paraneoplastic Neurologic Syndromes in Childhood.

BACKGROUND AND OBJECTIVES: Paraneoplastic neurologic syndromes (PNSs) are remote neurologic immune-related effects of tumors. The clinical characteristics of pediatric PNSs remain unclear. We retrospectively examined the clinical characteristics of cases of pediatric PNSs and assessed the performance of the 2021 diagnostic criteria in children. METHODS: Patients hospitalized in the Beijing Children's Hospital between June 2015 and June 2023 and fulfilling the description of definite by 2004 diagnostic criteria of PNSs were included. A retrospective analysis of clinical characteristics was conducted, and the 2021 diagnostic criteria were applied to rediagnostic stratification. RESULTS: Among the 42 patients included, the most common neurologic syndrome was opsoclonus-myoclonus syndrome (OMS) (62%), followed by rapidly progressive cerebellar syndrome (26%). Most tumors were neuroblastomas (88%), with few being ovarian teratomas (10%). Approximately 71% (30/42) of patients were classified as definite and 24% (10/42) as probable according to the 2021 criteria. All cases judged as probable exhibited rapidly progressive cerebellar ataxia with neuroblastoma. For OMS, chemotherapy was administered based on the tumor's risk stage, accompanied by regular infusion of IV gamma globulin and oral steroids following tumor diagnosis. Twenty-one patients underwent regular follow-ups over 4.92 (0.58-7.58) years. The initial hospitalization recorded a median score of 12 (7-14) on the Mitchell and Pike OMS rating scale, decreasing to 0 (0-5) at the final follow-up. In cases of rapidly progressive cerebellar syndrome, a similar therapeutic regimen was used. Nine patients underwent regular follow-ups over 4.42 (1.17-7.50) years. The mean modified Rankin scale score at first hospitalization was 4 (3-4), reducing to 1 (0-4) at the final follow-up. Only 17% (5/30) of patients across both groups exhibited poor response to this regimen. Among these 5 patients, 4 belonged to the low-risk group (without chemotherapy). DISCUSSION: OMS followed by rapidly progressive cerebellar ataxia are the most common forms of PNSs in children and are associated with neuroblastoma. An aggressive approach with multiple immunotherapies may improve the prognosis of neuroblastoma-associated PNSs. The 2021 criteria perform well in pediatric PNSs. However, we propose upgrading the classification of antibody-negative rapidly progressive cerebellar ataxia with neuroblastoma to definite diagnosis. This adjustment aims to further improve the diagnostic efficacy of this diagnostic criterion in childhood.

Interest of rare autoantibodies in autoimmune encephalitis and paraneoplastic neurological syndromes: the utility (or futility) of rare antibody discovery.

PURPOSE OF REVIEW: The increasing recognition and diagnosis of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) is partly due to neural autoantibody testing and discovery. The past two decades witnessed an exponential growth in the number of identified neural antibodies. This review aims to summarize recent rare antibody discoveries in the context of central nervous system (CNS) autoimmunity and evaluate the ongoing debate about their utility. RECENT FINDINGS: In the last 5 years alone 15 novel neural autoantibody specificities were identified. These include rare neural antibody biomarkers of autoimmune encephalitis, cerebellar ataxia or other movement disorders, including multifocal presentations. SUMMARY: Although the clinical applications of these rare antibody discoveries may be limited by the low number of positive cases, they still provide important diagnostic, prognostic, and therapeutic insights.

Changing landscape in the field of paraneoplastic neurology: Personal perspectives over a 35-year career.

Paraneoplastic neurologic syndromes are a group of rare disorders that have fascinated neurologists for more than a century. The discovery in the 1980s that many of these disorders occurred in association with antibodies against neuronal proteins revived the interest for these diseases. This chapter first traces the history of the paraneoplastic neurologic syndromes during the era that preceded the discovery of immune mechanisms and then reviews the immunologic period during which many of these syndromes were found to be associated with antibodies against intracellular onconeuronal proteins and pathogenic cytotoxic T-cell mechanisms. Alongside these developments, investigations on the antibody-mediated disorders of the peripheral nervous system, such as the myasthenic syndromes or neuromyotonia, provided suggestions for the study of the central nervous system (CNS) syndromes. These converging areas of research culminated with the groundbreaking discovery of a new category of CNS disorders mediated by antibodies against neuronal surface proteins or receptors. These disorders are not always paraneoplastic, and the understanding of these syndromes and mechanisms has changed the landscape of neurology and neurosciences.

Paraneoplastic autonomic neuropathies and GI dysmotility.

A number of the well-recognized autoimmune and paraneoplastic neurologic syndromes commonly involve the autonomic nervous system. In some cases, the autonomic nerves or ganglia are primary targets of neurologic autoimmunity, as in immune-mediated autonomic ganglionopathies. In other disorders such as encephalitis, autonomic centers in the brain may be affected. The presence of autonomic dysfunction (especially gastrointestinal dysmotility) is sometimes overlooked even though this may contribute significantly to the symptom burden in these paraneoplastic disorders. Additionally, recognition of autonomic features as part of the clinical syndrome can help point the diagnostic evaluation toward autoimmune and paraneoplastic etiologies. As with other paraneoplastic disorders, the clinical syndrome and the presence and type of neurologic autoantibodies help to secure the diagnosis and direct the most appropriate investigation for malignancy. Optimal management for these conditions typically includes aggressive treatment of the neoplasm, immunomodulatory therapy, and symptomatic treatments for orthostatic hypotension and gastrointestinal dysmotility.

Clinical approach to diagnosis of paraneoplastic neurologic syndromes.

The correct diagnosis of a paraneoplastic neurologic syndrome (PNS) first requires the identification of the syndrome as one of those defined as high-risk (previously called classical) or intermediate-risk for cancer in the 2021 PNS diagnostic criteria. Testing for neuronal antibodies should be restricted to these syndromes as indiscriminate request decreases the diagnostic value of the antibodies. Identifying onconeural (high-risk for cancer) or intermediate-risk for cancer antibodies supports the paraneoplastic diagnosis and mandates the search for an underlying cancer. Tumor screening must follow the published guidelines. Repeated screening is indicated in neurologic syndromes with onconeural antibodies and patients with high-risk for cancer neurologic syndromes unless they present neuronal antibodies which are not associated with cancer. Neuronal antibodies should be screened by immunohistochemistry and confirmed by immunoblot (intracellular antigens) or cell-based assay (CBA) (surface antigens). Positive results only by immunoblot or CBA should be taken with caution. Although the 2021 diagnostic criteria for PNS do not capture all PNS, as they do not allow to diagnose definite PNS neurologic syndromes without neuronal antibodies, the updated criteria represent a step forward to differentiate true PNS from neurologic syndromes that coincide in time with cancer diagnosis without having a pathogenic link.

Epidemiology of paraneoplastic neurologic syndromes.

Paraneoplastic neurologic syndromes (PNS), initially depicted as seemingly cryptic remote manifestations of malignancy, were first described clinically in the early 20th century, with pathophysiologic correlates becoming better elucidated in the latter half of the century. There remain many questions not only about the pathophysiology but also regarding the epidemiology of these conditions. The continuous discovery of novel autoantigens and related neurologic disease has broadened the association in classical PNS to include conditions such as paraneoplastic cerebellar degeneration. It has also brought into focus several other neurologic syndromes with a putative neoplastic association. These conditions are overall rare, making it difficult to capture large numbers of patients to study, and raising the question of whether incidence is increasing over time or improved identification is driving the increased numbers of cases. With the rise and increasing use of immunotherapy for cancer treatment, the incidence of these conditions is additionally expected to rise and may present with various clinical symptoms. As we enter an era of clinical trial intervention in these conditions, much work is needed to capture more granular data on population groups defined by socioeconomic characteristics such as age, ethnicity, economic resources, and gender to optimize care and clinical trial planning.

Paraneoplastic neurologic syndrome and autoantibody accompaniments of germ cell tumors.

Paraneoplastic neurologic syndromes (PNSs) are a group of diseases affecting the central and/or peripheral nervous system caused by immune-mediated processes directed toward antigens with shared expression in tumor and neural tissue. Germ cell tumors (GCTs) are associated with PNSs with varied clinical phenotypes. Early diagnosis of PNS is vital to potentially uncover and treat underlying tumors, improving the chances of recovery, and preventing permanent neurologic complications. In this chapter, we outline the pathophysiology and epidemiology of PNS. We briefly provide a summary of GCTs in males and females. We review the neural-specific autoantibodies and PNSs associated with GCTs and their clinical and radiologic accompaniments. We also provide an overview of the treatment and prognosis of these disorders.

Evaluation of potential prevalence of onconeural antibodies in women with breast cancer.

OBJECTIVE: Aim: To analyse onconeural antibodies in the blood serum of breast cancer patients without neurological symptoms.. PATIENTS AND METHODS: Materials and Methods: The study included 48 women with breast cancer. Paraneoplastic Neurologic Syndromes 12 Ag (IgG) Euroline by EUROIMMUN test was used to determine onconeural antibodies: anti-Hu, anti-Yo, anti-Ri, anti-CV2, anti-Ma/anti-Ta, anti-amphiphysin, anti-recoverin, anti-SOX1, anti-tytin, anti-zic4, anti-GAD65 and anti-Tr (DNER). RESULTS: Results: The conducted analysis revealed the presence of onconeural antibodies such as: anti-recoverin, anti-CV2, anti-Zic4, anti-SOX1, anti-MA2/Ta and antititin in blood serum of women with breast cancer. CONCLUSION: Conclusions: Further analysis may allow the assessment of the possible clinical usefulness of these determinations.

Management of Paraneoplastic Syndromes in the Era of Immune Checkpoint Inhibitors.

OPINION STATEMENT: Our understanding of paraneoplastic neurologic syndromes (PNS) has blossomed over the past few decades. Clinicians have access to more robust diagnostic criteria and have a heightened index of suspicion for these disorders. Nonetheless, treatment, which typically includes immunosuppression, and response to treatment, varies. Due to persistent difficulty in making a definitive diagnosis, we favor empiric treatment when a possible diagnosis of PNS is suspected, and other alternative causes have substantially been excluded (e.g., infections, toxic-metabolic derangements, metastasis, or leptomeningeal disease). Treatment of the underlying cancer, if identified, is the first therapeutic step and can prevent disease worsening and in rare cases, can reverse neurologic symptoms. In addition to anti-cancer treatment, first line immunotherapies, which include corticosteroids, intravenous immunoglobulins (IVIG), or plasma exchange (PLEX) are typically used. If partial or no benefit is seen, second line immunotherapeutic agents such as rituximab are considered. Additionally, the severity of the initial presentation and possible risk for relapse influences the use of the latter agents. Symptomatic management is also an important component in our practice and will depend on the syndrome being treated. One of the more novel entities we are facing currently is the management of immune checkpoint (ICI)-induced PNS. In those cases, current American Society of Clinical Oncology (ASCO) guidelines are followed.

Updates in the Management of Paraneoplastic Syndrome.

Paraneoplastic neurological syndromes (PNS) are defined as remote neurologic immune-mediated effects triggered by underlying systemic tumors. While recognizing specific syndromes can aid early cancer detection, overutilization of paraneoplastic assays in the absence of a classic syndrome can precipitate overdiagnosis and overtreatment. PNS involve autoantibodies targeting intracellular or extracellular antigens, with variable immunotherapy responses based on antigen type. Diagnosing PNS is challenging, requiring exclusion of other differential diagnoses. New diagnostic criteria classify PNS into high-risk and intermediate-risk phenotypes based on clinical phenotype, neuronal antibodies, and cancer presence. Patients with cell surface antibodies respond better to immunotherapies compared to those with intracellular antigen targets. Understanding PNS syndromes, serological markers, and oncological features guides management, which facilitates initiation of immunosuppression for PNS alongside treatment of the underlying neoplasm, thereby improving neurologic and oncologic outcomes. Initial treatments often include intravenous methylprednisolone, plasma exchange, or intravenous immunoglobulins. Second-line immunosuppressants like rituximab or cyclophosphamide may be necessary if initial treatments fail. Specific therapies vary based on antibody target. Here, we summarize the current approach to the investigation, diagnosis, and treatment of patients with suspected PNS.

Anti-Ri paraneoplastic neurological syndrome presenting with bilateral cranial nerve VI palsy and jaw dystonia-a distinctive syndrome within the anti-Ri spectrum? : Case report and literature review.

OBJECTIVE: Paraneoplastic neurological syndromes (PNS) are rare disorders associated with various onconeuronal antibodies. Anti-Ri antibodies (ANNA-2) are typically found in patients with opsoclonus myoclonus syndrome (OMS) and ataxia. CASE REPORT: We present an anti-Ri antibody-positive 77-year-old woman with subacute progressive bilateral cranial nerve VI palsy, gait disturbance and jaw dystonia. MRI of the brain showed hyperintense signals on T2 bitemporal without contrast enhancement. Cerebrospinal fluid (CSF) examination exhibited mild pleocytosis of 13 cells/µl and positive oligoclonal bands. CSF was overall inconspicuous for a malignant or inflammatory etiology. Immunofluorescence analysis revealed anti-Ri antibodies in both serum and CSF. Subsequent diagnostic work up resulted in a newly diagnosed ductal carcinoma of the right breast. PNS in this case partially responded to the anti-tumor therapy. CONCLUSION: This case shows similarities with recently published anti-Ri syndromes, which might form a distinct triad within the anti-Ri spectrum.

Paraneoplastic syndromes associated with classic Hodgkin lymphoma, a systematic literature review.

PNS are uncommon manifestations of cancer. The current literature about these syndromes in the setting of cHL is disintegrated. A systematic literature review of all published literature was conducted. One hundred twenty-eight patients from 115 publications met the inclusion/exclusion criteria. Eight-five patients were of the NS subtype (66.4%). The most frequent clinical presentation of the PNS was CNS manifestation (25.8%). The majority of patients were diagnosed with the cHL and PNS simultaneously (42.2%). In 33.6% of patients, the lymphoma diagnosis preceded the PNS diagnosis. In 16.4% of patients, the PNS diagnosis preceded the lymphoma diagnosis. The presence of PNS antibodies was reported in 35 patients (27.3%). Age older than 18 was associated with higher prevalence of PNS. The CR rate of the lymphoma was 77.3%. The complete resolution rate of the PNS was 54.7%. Relapse of lymphoma was reported in 13 patients, and recurrence of the PNS upon relapse was reported in 10/13 patients.

Autonomic nervous system involvement in autoimmune encephalitis and paraneoplastic neurological syndromes.

In autoimmune neurological diseases, the autonomic nervous system can be the primary target of autoimmunity (e.g. autoimmune autonomic ganglionopathy), or, more frequently, be damaged together with other areas of the nervous system (e.g. Guillain-Barré syndrome). Patients with autoimmune encephalitis and paraneoplastic neurological syndromes (PNS) often develop dysautonomia; however, the frequency and spectrum of autonomic signs and symptoms remain ill defined except for those scenarios in which dysautonomia is a core feature of the disease. Such is the case of Lambert-Eaton myasthenic syndrome, Morvan syndrome or anti-NMDAR encephalitis; in the latter, patients with dysautonomia have been reported to carry a more severe disease and to retain higher disability than those without autonomic dysfunction. Likewise, the presence of autonomic involvement indicates a higher risk of death due to neurological cause in patients with anti-Hu PNS. However, in anti-Hu and other PNS, as well as in the context of immune checkpoint inhibitors' toxicities, the characterization of autonomic involvement is frequently overshadowed by the severity of other neurological symptoms and signs. When evaluated with tests specific for autonomic function, patients with autoimmune encephalitis or PNS usually show a more widespread autonomic involvement than clinically suggested, which may reflect a potential gap of care when it comes to diagnosing dysautonomia. This review aims to revise the autonomic involvement in patients with autoimmune encephalitis and PNS, using for that purpose an antibody-based approach. We also discuss and provide general recommendations for the evaluation and management of dysautonomia in these patients.

Paraneoplastic Neurologic Syndromes.

OBJECTIVE: Progress is ongoing in understanding paraneoplastic neurologic disorders, with new syndromes and antibodies being described and more detailed evidence available to guide workup for diagnosis and treatment to improve outcomes. Many excellent reviews have summarized the molecular features of different antibodies, but this article emphasizes the clinical features of each syndrome that may help guide initial diagnosis and treatment, which often should occur before an antibody or cancer is found to confirm the diagnosis. LATEST DEVELOPMENTS: Recent findings include updated diagnostic criteria with validated sensitivity and specificity, discovery of novel antibodies, and clinical findings that increase the likelihood of an underlying paraneoplastic disorder. Suggestive syndromes that have been recently identified include faciobrachial dystonic seizures and pilomotor auras in anti-leucine-rich glioma inactivated protein 1 encephalitis, extreme delta brush on EEG in N-methyl-d-aspartate (NMDA)-receptor encephalitis, déjà vu aura in anti-glutamic acid decarboxylase 65 (GAD65) encephalitis, and sleep disturbances in several disorders. In addition, there is confirmed utility of brain positron emission tomography (PET) and CSF markers, including carcinoembryonic antigen and oligoclonal bands, as well as improved tests for the presence of leptomeningeal cancer cells in CSF. Associations of cancer immunotherapies with paraneoplastic syndromes and herpes simplex virus encephalitis (and COVID-19) with NMDA-receptor encephalitis have been described. ESSENTIAL POINTS: All neurologists should be aware of advances regarding paraneoplastic neurologic syndromes, as patients can present with a wide variety of neurologic symptoms and earlier diagnosis and treatment can improve outcomes.

Seronegative paraneoplastic encephalomyelitis in occult colonic carcinoma.

Paraneoplastic neurological syndromes are immune-mediated neurological attacks triggered by malignancies. They are commonly associated with lung, breast, thymus, gynaecological and haematological malignancies. We report a case of a male patient in his late 40s with paraneoplastic encephalomyelitis due to a colonic adenocarcinoma emphasising a low threshold for extensive cancer evaluation in all subacutely presenting neurological syndromes. We also emphasise that the absence of a positive onconeural antibody does not preclude the diagnosis of a paraneoplastic syndrome.

[Paraneoplastic Neurologic Syndromes].

Paraneoplastic neurologic syndromes (PNS) are a group of neurological disorders that are possibly caused by immunological mechanisms triggered by an underlying tumor that involves every part of the nervous system. Autoantibodies were categorized according to the risk of cancer association. Antibodies against intracellular proteins are excellent markers for tumor detection, however, without functional roles in neuronal loss, the direct effector of neuronal damage is thought to be cytotoxic T cells. The frequently associated symptoms include limbic encephalitis, cerebellar ataxia and sensory neuronopathy. The associated tumors are mainly small-cell lung cancer, breast/ovarian/uterine cancers, and thymoma. Timely diagnosis, prompt immunotherapy, and treatment of the underlying tumor are essential for managing PNS. However, we need to be cautious about the high frequency of false-positive/negative results of antibodies using commercial antibody tests. This highlight the importance of the careful evaluation of clinical features. Recently, PNS emerged after immune check point inhibitor administration, and this became a subject of attention exploring its pathogenesis. Other basic studies to understand the immunological background of PNS have been progressing.